This application is a 371 of PCT/JP98/05779, filed Dec. 21, 1998.
The present invention generally relates to pharmaceutical compositions comprising as an active ingredient a compound having purine structure, and specifically relates to a type 2 helper T cell (hereinafter abbreviated to xe2x80x9cTh2xe2x80x9d)-selective immune response inhibitor and an immune response regulator. More specifically, the present invention relates to a Th2-selective immune response inhibitor and an immune response regulator which can effectively treat or prevent those diseases attributable to abnormal rise immunize response on the Th2 side (i.e. allergic diseases such as asthma, allergic dermatitis or allergic rhinitis, or autoimmune diseases such as systemic lupus erythematosus) by inhibiting immune response on the Th2 side and enhancing immune response on the type 1 helper T cell (hereinafter abbreviated to xe2x80x9cTh1xe2x80x9d) side.
What is playing the major role in immune response is helper T cells. There are two classes, Th1 and Th2, in helper T cells. Cytokines produced when Th1 is activated include interleukin-2 (IL-2) and interferon-xcex3 (IFN-xcex3); and cytokines produced when Th2 is activated include interleukin-4 (IL-4) and interleukin-5 (IL-5). Cytokines on the Th1 side induce activation of macrophages and natural killer cells, and are mainly involved in cellular immunity such as infection control against viruses and bacteria. On the other hand, it is known that cytokines on the Th2 side are involved in humoral immunity such as antibody production from B cells. Particularly, IL-4 not only induces production of IgE antibody by B cells, but also has an action of differentiating and proliferating Th2 cells. IL-5 has various actions such as activation, differentiation/proliferation and lifetime prolongation of eosinophils, and plays an important role in allergic inflammation. Thus, it is considered that allergic inflammation is caused by abnormal rise in immune response on the Th2 side. Actually, the presence of IL-4 and IL-5 has been confirmed in affected parts of asthma patients and patients with atopic dermatitis.
Conventionally, asthma, atopic dermatitis and the like have been treated with anti-allergic agents. However, such agents do not inhibit the immune response by Th2; as in the case of histamine, they only inhibit a part of allergic reactions in the downstream. Thus, their clinical effect is insufficient. Consequently, only steroids have been proved effective against these diseases. However, long term administration of steroids causes wide-ranging side effects (diabetes, infections, adrenal dysfunction, moon face, etc.). Since steroids inhibit immune response on both the Th1 side and the Th2 side, administration of steroids results in the lowering of patients"" resistance to viral infections as their immune response is lowered. In order to overcome this drawback, a drug which inhibits immune response on the Th2 side and simultaneously enhances immune response on the Th1 side can be said more preferable since such a drug has an advantage of preventing infections caused by virus or the like.
From what has been described so far, it is considered that if a drug which enhances immune response on the Th1 side represented by production of IFN-xcex3 and inhibits immune response on the Th2 side represented by production of IL-4 and IL-5 is developed, the drug will be an effective and highly safe therapeutic or prophylactic for allergic diseases
Autoimmune diseases such as systemic lupus erythematosus are also presumed to be a state in which immune response on the Th2 side has been abnormally exasperated (Medical Immunology, 15, 401, 1985). Thus, a drug which enhances immune response on the Th1 side and inhibits immune response on the Th2 side as described above is expected to be a therapeutic for autoimmune diseases.
Under such circumstances, it is an object of the present invention to provide an effective therapeutic for allergic diseases caused by abnormal rise in immune response on the Th2 side, which therapeutic treats allergic diseases by enhancing immune response on the Th1 side represented by production of IFN-xcex3, etc. and simultaneously inhibiting immune response on the Th2 side represented by production of IL-4, IL-5, etc.
As a result of extensive and intensive researches to develop a drug which enhances immune response on the Th1 side represented by production of IFN-xcex3, etc. and simultaneously inhibits immune response on the Th2 side represented by production of IL-4, IL-5, etc., the prevent inventors have found that purine derivatives having a specific structure enhance immune response on the Th1 side and inhibit immune response on the Th2 side. Thus, the present invention has been achieved.
The present invention relates to a type 2 helper T cell-selective immune response inhibitor and an immune response regulator, individually comprising, as an active ingredient, a purine derivative represented by General Formula (I): 
wherein
R2 is hydrogen or a C1-14 hydrocarbon group in which xe2x80x94CH2xe2x80x94 not directly bound to the purine skeleton and CH2 in xe2x80x94CH3 not directly bound to the purine skeleton may be substituted by carbonyl, sulfonyl, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; xe2x95x90CH2 may be substituted by xe2x95x90O or xe2x95x90S; Cxe2x80x94H in xe2x80x94CH2xe2x80x94 not directly bound to the purine skeleton, Cxe2x80x94H in xe2x80x94CH3 not directly bound to the purine skeleton, Cxe2x80x94H in  greater than CHxe2x80x94 not directly bound to the purine skeleton, Cxe2x80x94H in xe2x95x90CHxe2x80x94 not directly bound to the purine skeleton and Cxe2x80x94H in xe2x95x90CH2 may be substituted by N, C-halogen or Cxe2x80x94CN;
R6 is hydroxyl, amino or amino which is mono- or di-substituted by a C1-10 hydrocarbon group(s);
R8 is hydroxyl, mercapto, C1-18 acyloxy or C1-19 hydrocarbon group-substituting oxycarbonyloxy; and
R9 is a C1-14 hydrocarbon group in which xe2x80x94CH2xe2x80x94 not directly bound to the purine skeleton and CH2 in xe2x80x94CH3 not directly bound to the purine skeleton may be substituted by carbonyl, sulfonyl, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; xe2x95x90CH2 may be substituted by xe2x95x90O or xe2x95x90S; Cxe2x80x94H in xe2x80x94CH2xe2x80x94 not directly bound to the purine skeleton, Cxe2x80x94H in xe2x80x94CH3 not directly bound to the purine skeleton, Cxe2x80x94H in  greater than CHxe2x80x94 not directly bound to the purine skeleton, Cxe2x80x94H in xe2x95x90CHxe2x80x94 not directly bound to the purine skeleton, Cxe2x80x94H in xe2x95x90CH2 and Cxe2x80x94H in xe2x89xa1CH may be substituted by N, C-halogen or Cxe2x80x94CN;
or its tautomer or a pharmaceutically acceptable salt of the purine derivative or the tautomer.
Specifically, the Th2-selective immune response inhibitor and the immune response regulator of the invention are used as an anti-allergic agent; they are pharmaceuticals to be administered for alleviating the conditions of allergic diseases developed by various causes or for preventing the manifestation of symptoms. Specifically, the above-mentioned allergic diseases include allergic dermatitis, allergic rhinitis, atopic dermatitis, asthma (atopic asthma, non-atopic asthma) and the like. The Th2-selective immune response inhibitor and the immune response regulator of the invention are used as a therapeutic or prophylactic for such diseases. Furthermore, they are used as a therapeutic or prophylactic for autoimmune diseases such as systemic lupus erythematosus having similar uncomfortable symptoms.
Hereinbelow, the purine derivative represented by General Formula (I) which is used as an active ingredient in the present invention will be described in more detail.
First, the hydrocarbon group in General Formula (I) described above includes any of straight- or branched-chain hydrocarbon groups; monocyclic hydrocarbon groups without or with a side chain(s); polycyclic hydrocarbon groups without or with a side chain(s); spiro hydrocarbon groups without or with a side chain(s); ring-assembling structural hydrocarbon groups without or with a side chain(s); or chain hydrocarbon groups substituted by the above-described cyclic hydrocarbon group(s). The hydrocarbon group in General Formula (I) also includes both saturated hydrocarbon groups and unsaturated hydrocarbon groups, but it does not include those unsaturated hydrocarbon groups which have the ketine structure Cxe2x95x90Cxe2x95x90C. Specific examples of straight- or branched-chain hydrocarbon groups include straight-chain alkyl with 1 or more carbon atoms, branched-chain alkyl with 3 or more carbon atoms (which are saturated chain hydrocarbon groups); straight-chain alkenyl with 2 or more carbon atoms, branched-chain alkenyl with 3 or more carbon atoms, straight-chain alkynyl with 3 or more carbon atoms, branched-chain alkynyl with 4 or more carbon atoms, straight-chain alkadienyl with 4 or more carbon atoms, and branched-chain alkadienyl with 5 or more carbon atoms (which are unsaturated chain hydrocarbon groups). Specific examples of monocyclic hydrocarbon groups include cycloalkyl with no side chain and with 3 or more carbon atoms and cycloalkyl with a side chain(s) and with 4 or more carbon atoms in total (which are saturated monocyclic hydrocarbon groups); cycloalkenyl with no side chain and with 4 or more carbon atoms, cycloalkynyl with a side chain(s) and with 5 or more carbon atoms in total, cycloalkadienyl with no side chain and with 5 or more carbon atoms and cycloalkadienyl with a side chain(s) and with 6 or more carbon atoms in total (which are unsaturated monocyclic hydrocarbon groups). As aromatic hydrocarbon groups, aromatic groups with no side chain and with 6-14 carbon atoms in total (such as phenyl, 1-naphthyl, 2-naphthyl and 9-anthryl); and aromatic groups with a side chain(s) and with 7 or more carbon atoms in total may be enumerated, for example. Further, phenylphenyl with no side chain and with 12 carbon atoms and phenylphenyl with a side chain(s) and with 13 or more carbon atomsin total (which are also ring-assembling structural hydrocarbon groups) may be enumerated. Specific examples of polycyclic hydrocarbon groups include condensed cyclic hydrocarbon groups with no side chain and with 6 or more carbon atoms; condensed cyclic hydrocarbon groups with a side chain(s) and with 7 or more carbon atoms in total; crosslinked cyclic hydrocarbon groups with no side chain and with 7 or more carbon atoms; crosslinked cyclic hydrocarbon groups with a side chain(s) and with 8 or more carbon atoms in total; spiro hydrocarbon groups with no side chain and with 9 or more carbon atoms; and spiro hydrocarbon groups with a side chain(s) and with 10 or more carbon atoms in total. When one of the condensed rings is a benzene ring in the above-mentioned condensed cyclic hydrocarbon group with no side chain, those hydrocarbon groups with 9 or more carbon atoms in total may be enumerated as specific examples; when one of the condensed rings is a benzene ring in the above-mentioned condensed cyclic hydrocarbon group with a side chain(s), those hydrocarbon groups with 10 or more carbon atoms in total may be enumerated as specific examples. As ring-assembling structural hydrocarbon groups, cycloalkylcycloalkyl with no side chain and with 6 or more carbon atoms in total; cycloalkylcycloalkyl with a side chain(s) and with 7 or more carbon atoms in total; cycloalkylidenecycloalkyl with no side chain and with 6 or more carbon atoms in total; cycloalkylidenecycloalkyl with a side chain(s) and with 7 or more carbon atoms in total; and the like may be enumerated. In these cyclic hydrocarbons, xe2x80x9cwith a side chain(s)xe2x80x9d means that the cyclic hydrocarbon has a chain hydrocarbon(s) on its ring. Specific examples of the chain hydrocarbon groups substituted by the above-described cyclic hydrocarbon group(s) include straight-chain alkyl substituted by an aromatic group that has no side chain and 7 or more carbon atoms in total; straight-chain alkyl substituted by an aromatic group that has a side chain(s) and 8 or more carbon atoms in total; branched-chain alkyl substituted by an aromatic group that has no side chain and 9 or more carbon atoms in total; branched-chain alkyl substituted by an aromatic group that has a side chain(s) and 10 or more carbon atoms in total; straight-chain alkenyl substituted by an aromatic group has no side chain and 8 or more carbon atoms in total; straight-chain alkenyl substituted by an aromatic group that has a side chain(s) and 9 or more carbon atoms in total; branched-chain alkenyl substituted by an aromatic group that has no side chain and 9 or more carbon atoms in total; branched-chain alkenyl substituted by an aromatic group that has a side chain(s) and 10 or more carbon atoms in total; straight-chain alkynyl substituted by an aromatic group that has no side chain and 8 or more carbon atoms in total; straight-chain alkynyl substituted by an aromatic group that has a side chain(s) and 9 or more carbon atoms in total; branched-chain alkynyl substituted by an aromatic group that has no side chain and 10 or more carbon atoms in total; branched chain alkynyl substituted by an aromatic group that has a side chain(s) and 11 or more carbon atoms in total; straight-chain alkadienyl substituted by an aromatic group that has no side chain and 10 or more carbon atoms in total; straight-chain alkadienyl substituted by an aromatic group that has a side chain(s) and 11 or more carbon atoms in total; branched-chain alkadienyl substituted by an aromatic group that has no side chain and 11 or more carbon atoms in total; branched chain alkadienyl substituted by an aromatic group that has a side chain(s) and 12 or more carbon atoms in total; straight-chain alkyl substituted by cycloalkyl that has no side chain and 4 or more carbon atoms in total; straight-chain alkyl substituted by cycloalkyl that has a side chain(s) and 5 or more carbon atoms in total; branched-chain alkyl substituted by cycloalkyl that has no side chain and 6 or more carbon atoms in total; branched-chain alkyl substituted by cycloalkyl that has a side chain(s) and 7 or more carbon atoms in total; straight-chain alkenyl substituted by cycloalkyl that has no side chain and 5 or more carbon atoms in total; straight-chain alkenyl substituted by cycloalkyl that has a side chain(s) and 6 or more carbon atoms in total; branched-chain alkenyl substituted by cycloalkyl that has no side chain and 6 or more atoms in total; branched-chain alkenyl substituted by cycloalkyl that has a side chain(s) and 7 or more carbon atoms in total; straight-chain alkynyl substituted by cycloalkyl that has no side chain and 5 or more carbon atoms in total; straight-chain alkynyl substituted by cycloalkyl that has a side chain(s) and 6 or more carbon atoms in total; branched-chain alkynyl substituted by cycloalkyl that has no side chain and 7 or more carbon atoms in total; branched-chain alkynyl substituted by cycloalkyl that has a side chain(s) and 8 or more carbon atoms in total; straight-chain alkadienyl substituted by cycloalkyl that has no side chain and 7 or more carbon atoms in total; straight-chain alkadienyl substituted by cycloalkyl that has a side chain(s) and 8 or more carbon atoms in total; branched-chain alkadienyl substituted by cycloalkyl that has no side chain and 8 or more carbon atoms in total; and branched-chain alkadienyl substituted by cycloalkyl that has a side chain(s) and 9 or more carbon atoms in total.
Hereinbelow, aromatic groups with no side chain, aromatic groups with a side chain(s), phenylphenyl with no side chain, phenylphenyl with a side chain(s), and the like will be collectively called xe2x80x9carylxe2x80x9d. Also, straight- or branched-chain alkyl substituted by aryl will be called xe2x80x9caralkylxe2x80x9d. Similarly, unless otherwise indicated, other cyclic hydrocarbon groups will be called merely xe2x80x9ccycloalkylxe2x80x9d or the like when both hydrocarbon groups with no side chain and hydrocarbon groups with a side chain(s) are meant. Chain hydrocarbon groups will also be called merely xe2x80x9calkylxe2x80x9d or the like when both straight-chain and branched-chain hydrocarbon groups are meant.
In the above-mentioned hydrocarbon group, when xe2x80x94CH2xe2x80x94 is substituted by carbonyl, sulfonyl, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, ketone, sulfone, ether or thioether structure is introduced, respectively; when xe2x80x94CH2xe2x80x94 in xe2x80x94CH3 is substituted by carbonyl, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, the xe2x80x94CH3 is converted to formyl (aldehyde), hydroxyl or mercapto, respectively; when terminal xe2x95x90CH2 is substituted by xe2x95x90O or xe2x95x90S, ketone or thioketone structure is introduced. Further, in the above-mentioned hydrocarbon group, when Cxe2x80x94H in xe2x80x94CH3xe2x80x94 is changed to N, xe2x80x94NHxe2x80x94 is generated; when Cxe2x80x94H in  greater than CHxe2x80x94 is changed to N,  greater than Nxe2x80x94 is generated; when Cxe2x80x94H in xe2x95x90CHxe2x80x94 is changed to N, xe2x95x90Nxe2x80x94 is generated; when Cxe2x80x94H in terminal xe2x80x94CH3 is changed to N, xe2x80x94NH2 is introduced; when Cxe2x80x94H in xe2x95x90CH2 is changed to N, xe2x95x90NH is generated; when Cxe2x80x94H in Cxe2x89xa1CH is substituted by N, the Cxe2x95x90CH is converted to Cxe2x89xa1N (cyano). When Cxe2x80x94H in xe2x80x94CH3, xe2x80x94CH2xe2x80x94, xe2x95x90CHxe2x80x94, xe2x89xa1CH or  greater than CHxe2x80x94 is substituted by C-halogen or Cxe2x80x94CN, halogeno or cyano is substituted on the relevant carbon. Substitution with xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or N in the carbon chain corresponds to oxa-substitution, thia-substitution or aza-substitution of the relevant hydrocarbon group, respectively. For example, when such substitution occurs in one of the skeleton carbons forming a hydrocarbon ring, the hydrocarbon ring is converted to an oxygen-containing heterocycle, sulfur-containing heterocycle or nitrogen-containing heterocycle. In the above-mentioned hydrocarbon group, substitution in CH2 and substitution in Cxe2x80x94H may be performed independently. Besides, if CH2 or Cxe2x80x94H still remains on the relevant hydrocarbon group after the above substitution, further substitution may be performed. Furthermore, conversion of xe2x80x94CH2xe2x80x94CH2xe2x80x94 to xe2x80x94COxe2x80x94Oxe2x80x94 (ester structure) or xe2x80x94COxe2x80x94Sxe2x80x94 (thioester structure); conversion of xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 to xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94 (carbonic acid ester structure) or xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94 (urea structure) (ureylene); conversion of xe2x80x94CH2xe2x80x94CH3 to xe2x80x94COxe2x80x94Oxe2x80x94H (carboxylic acid structure), xe2x80x94COxe2x80x94NH2 (amide structure) or xe2x80x94SO2xe2x80x94NH2 (sulfonamide structure), and the like may be performed by the above-mentioned substitution. Halogen means fluorine, chlorine, bromine and iodine, among which fluorine, chlorine and bromine are preferable.
Accordingly, as the C1-14 hydrocarbon group represented by R2 or R9 in General Formula (I) described above, either a chain hydrocarbon group or a hydrocarbon group with a cyclic structure (such as cyclic hydrocarbon group) may be selected. Specific examples of the C1-14 hydrocarbon group include straight- or branched-chain alkyl (saturated chain hydrocarbon group); straight- or branched-chain alkenyl, straight- or branched-chain alkynyl, straight- or branched-chain alkadienyl and the like (unsaturated chain hydrocarbon groups); cycloalkyl (saturated cyclic hydrocarbon group); cycloalkenyl, cycloalkynyl, cycloalkadienyl and the like (unsaturated cyclic hydrocarbon groups); and aryl, aralkyl, arylalkenyl and the like (aromatic cyclic hydrocarbon groups).
More specifically, as straight- or branched-chain alkyl, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, pentyl, 1-methylbutyl, hexyl, 1-methylpentyl, heptyl, 1-methylhexyl, 1-ethylpentyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, methylhexyl, methylheptyl, methyloctyl, methylnonyl, 1,1-dimethylethyl, 1,1-dimethylpropyl, 2,6-dimethylheptyl, 3,7-dimethyloctyl, 2-ethylhexyl or the like may be enumerated. As cycloalkylalkyl, cyclopentylmethyl, cyclohexylmethyl or the like may be enumerated. As cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, cyclooctyl or the like may be enumerated. As bicycloalkyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl or the like may be enumerated. As straight- or branched-chain alkenyl, vinyl, allyl, crotyl (2-butenyl), isopropenyl (1-methylvinyl) or the like may be enumerated. As cycloalkenyl or cycloalkadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexanedienyl or the like may be enumerated. As straight- or branched-chain alkynyl, ethynyl, propynyl, butynyl, or the like may be enumerated. As aryl, phenyl, 1-naphthyl, 2-naphthyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 9-anthryl, methylphenyl, dimethylphenyl, trimethylphenyl, ethylphenyl, ethylmethylphenyl, diethylphenyl, propylphenyl, butylphenyl or the like may be enumerated. As aralkyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl (2-phenylethyl), 1-phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, methylbenzyl, methylphenethyl, dimethylbenzyl, dimethylphenethyl, trimethylbenzyl, ethylbenzyl, diethylbenzyl or the like may be enumerated. As arylalkenyl, styryl, methylstyryl, ethylstyryl, dimethylstyryl, 3-phenyl-2-propenyl or the like may be enumerated.
As the hydrocarbon group represented by R2 or R9 in which CH2 is substituted by carbonyl, sulfonyl, O or S, or in which Cxe2x80x94H is substituted by N, C-halogen or Cxe2x80x94CN, a group may be given that contains one or more structures such as ketone, aldehyde, carboxylic acid, ester, thioester, amide, carbonic acid ester, carbamic acid ester, sulfone, sulfonamide, ether, thioether, amine, alcohol, thiol, halogen, oxygen-containing heterocycle, sulfur-containing heterocycle or nitrogen-containing heterocycle structure. The oxygen-containing heterocycle, sulfur-containing heterocycle or nitrogen-containing heterocycle means one of the carbons constituting the ring skeleton in a cyclic hydrocarbon group is substituted by oxygen, sulfur or nitrogen, respectively. Further, such a heterocycle may have two or more heteroatom substitutions. Specific examples of hydrocarbon groups having the above-mentioned substitution include acetylmethyl of ketone structure; methanesulfonylmethyl of sulfone structure; methoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, butoxyethyl and ethoxyethoxyethyl of ether structure; methylthiomethyl of thioether structure; methylaminomethyl, dimethylaminomethyl, methylaminoethyl, propylaminomethyl and cyclopentylaminomethyl of amine structure; methoxycarbonylmethyl and acetoxymethyl of ester structure; acetylaminomethyl and acetylaminoethyl of amido structure; tetrahydrofuranyl, tetrahydropyranyl and morpholylethyl of oxygen-containing heterocyclic structure; methoxyphenyl of ether structure; methylthiophenyl of thioether structure; acetylphenyl of ketone structure; methoxycarbonyloxyphenyl and ethoxycarbonyloxyphenyl of carbonic acid ester structure; dimethoxyphenyl; methoxycarbonylphenyl, acetoxyphenyl and methylaminocarbonylphenyl of ester structure; furyl of oxygen-containing aromatic ring structure; thienyl of sulfur-containing aromatic ring structure; pyrrolyl, benzofuranyl, imidazolyl, oxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, tetrazinyl, quinolyl, isoquinolyl, pyridylmethyl, phenoxymethyl and benzoyloxymethyl of nitrogen-containing aromatic ring structure; 2-hydroxyethyl of alcohol structure; 2-mercaptoethyl of thiol structure; 2-aminoethyl of amine structure; 2-chloroethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-mercaptopropyl, 3-mercaptopropyl, 2-aminopropyl, 3-aminopropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dihydroxypropyl, 2,3-dimercaptopropyl, 2,3-diaminopropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl, 2-mercaptobutyl, 3-mercaptobutyl, 4-mercaptobutyl, 2-chlorobutyl, 3-chlorobutyl, 4-chlorobutyl, 2,3-dihydroxybutyl, 2,4-dihydroxybutyl, 3,4-dihydroxybutyl, 2,3-diaminobutyl, 2,4-diaminobutyl, 3,4-diaminobutyl, 2-amino-3-hydroxybutyl, 3-amino-2-hydroxybutyl, 2-amino-4-hydroxybutyl, 4-amino-2-hydroxybutyl, 3-amino-4-hydroxybutyl, 4-amino-3-hydroxybutyl, 2,3,4-trihydroxybutyl, 2,3,4-triaminobutyl, 2,4-diamino-3-hydroxybutyl, 3-amino-2,4-dihydroxybutyl, 2,3-diamino-4-hydroxybutyl, 4-amino-2,3-dihydroxybutyl, 3,4-diamino-2-hydroxybutyl, 2-amino-3,4-dihydroxybutyl, aminosulfonylphenyl, hydroxyphenyl, aminophenyl, mercaptophenyl, fluorophenyl, chlorophenyl, bromophenyl, cyanophenyl, dihydroxyphenyl, diaminophenyl, difluorophenyl, dichlorophenyl, dibromophenyl, chlorofluorophenyl, trifluorophenyl, trichlorophenyl, fluoromethylphenyl, trifluoromethylphenyl, aminomethylphenyl, hydroxymethylphenyl, hydroxyethylphenyl, aminohydroxyphenyl, fluorohydroxyphenyl, chlorohydroxyphenyl, hydroxycarbonylphenyl and aminocarbonylphenyl.
As preferable examples of R2 in General Formula (I) described above, non-substituted or substituted straight- or branched-chain alkyl, alkenyl or alkadienyl may be enumerated in addition to hydrogen. Specifically, lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and pentyl; cycloalkyl; cycloalkylalkyl; aryl; and aralkyl, especially non-substituted or substituted benzyl, may be enumerated. Further, Cxe2x80x94H in the benzene ring of the above-mentioned benzyl may be substituted by nitrogen. Also, hydrogen on the benzene ring may be substituted by amine. Alternatively, it may be substituted by methyl or the like as a side chain on the ring. In other words, substituted benzyl such as 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl; or aza-substituted groups such as 2-pyridylmethyl, 3-pyridylmethyl and 4-pyridylmethyl obtainable by substituting CH of the benzene ring in non-substituted or substituted benzyl by nitrogen are also preferable as R2.
As preferable examples of R9 in General Formula (I) described above, non-substituted or substituted alkyl, in particular, lower alkyl, alkenyl, alkadienyl, cycloalkyl, aryl, aralkyl, in particular, benzyl and substituted benzyl, may be enumerated. Further, Cxe2x80x94H in the benzene ring in the above-mentioned benzyl may be substituted by nitrogen; hydrogen on the ring may be substituted by halogeno (particularly, chloro, bromo, fluoro), trifluoromethyl, amino or the like; and lower alkyl such as methyl may be substituted on the ring as a side chain. Besides, alkyl substituted by an aromaticity-exhibiting oxygen-containing heterocycle, sulfur-containing heterocycle or nitrogen-containing heterocycle (which alkyl resembles aralkyl) and the alkyl which further has a substituent(s) or a side chain(s) on the heterocycle are also preferable as R9. Specifically, preferable examples of substituted benzyl include 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2, 3-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 4-amino-3-chlorobenzyl, 3-amino-4-chlorobenzyl, 4-amino-3-bromobenzyl, 3-amino-4-bromobenzyl, and aza-substituted groups such as 2-pyridylmethyl, 3-pyridylmethyl and 4-pyridylmethyl obtainable by substituting Cxe2x80x94H of the benzene ring in non-substituted or substituted benzyl by nitrogen. Further, in the above-described alkyl substituted by an aromaticity-exhibiting oxygen-containing heterocycle, sulfur-containing heterocycle or nitrogen-containing heterocycle (which alkyl resembles aralkyl) and the alkyl which further has a substituent(s) on the heterocycle, specific examples of the aromaticity-exhibiting oxygen-containing heterocycle, sulfur-containing heterocycle or nitrogen-containing heterocycle constituting such alkyl include furan ring, thiophene ring and pyrrole ring (which are one heteroatom-substituted five-membered rings); oxazole ring, thiazole ring, imidazole ring, isooxazole ring, isothiazole ring and pyrazole ring (which are two heteroatoms-substituted five-membered rings); pyridine ring (which is a mono-aza-substituted benzene ring); pyrimidine ring, pyrazine ring and pyridazine ring (which are di-aza-substituted benzene rings); triazine ring (which is a tri-aza-substituted benzene ring); condensed bicyclic systems formed by condensation of one of these monocycles with the above-mentioned five-membered ring or benzene ring or its aza-substituted six-membered ring (e.g. those formed by condensation of a five-membered ring with a six-membered ring, such as benzofuran, benzothiophene, benzopyrole or benzoimidazole ring; and various azanaphthalene rings, such as quinoline ring, isoquinoline ring and quinoxaline ring, which correspond to aza-substituted forms of naphthalene ring formed by condensation of two six-membered rings); and 4H-pyran-4-one structure or the like which forms with oxo group substituted on the ting a conjugated system resembling an aromatic ring or a structure such as 1,4-dithianaphthalene ring which forms as a whole a conjugated system resembling an aromatic ring. In this alkyl substituted by an aromaticity-exhibiting oxygen-containing heterocycle, sulfur-containing heterocycle or nitrogen-containing heterocycle, a structure resembling non-substituted or substituted benzyl (i.e. methyl group substituted by, in particular, a monocycle of the above-mentioned aromaticity-exhibiting oxygen-containing heterocycle. sulfur-containing heterocycle or nitrogen-containing heterocycle) is regarded as more preferable as non-substituted or substituted benzyl. Further, a preferable substituent(s) or a side chain(s) in substituted benzyl may be substituted on the ring of the above-mentioned structure.
In the amino represented by R6 which is mono- or di-substituted by a C1-10 hydrocarbon group(s), the hydrocarbon group means a hydrocarbon group with 10 or less carbon atoms among the various hydrocarbon groups described above. Specific examples of the amino represented by R6 which is mono-substituted by a C1-10 hydrocarbon group include methylamino, ethylamino, propylamino, allylamino, butylamino, pentylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, norbornylamino, bicyclo[2.2.2]octyl amino, phenylamino, naphthylamino, (methylphenyl)amino, (dimethylphenyl)amino, (ethylphenyl)amino, benzylamino, (methylbenzyl) amino, (dimethylbenzyl)amino, (ethylbenzyl)amino and phenetylamino. Specific examples of the amino represented by R6 which is di-substituted by C1-10 hydrocarbon groups include dimethylamino, diethylamino, dipropylamino, diallylamino, dibutylamino, methylpropylamino, diphenylamino, bis(methylphenyl)amino, dibenzylamino, bis(methylbenzyl)amino, phenylmethylamino and benzylmethylamino.
The C1-18 acyloxy represented by R8 means oxy that has been substituted by acyl resulted from substitution of a C1-17 hydrocarbon group selected from the above-described hydrocarbon groups or hydrogen by carbonyl. Specific examples of the C1-18 acyloxy include formyloxy, acetyloxy, propionyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy, tridecanoyloxy, tetradecanoyloxy, pentadecanoyloxy, hexadecanoyloxy, heptadecanoyloxy, octadecanoyloxy, 2,2-dimethylpropanoyloxy, benzoyloxy, methylbenzoyloxy, dimethylbenzoyloxy, trimethylbenzoyloxy, ethylbenzoyloxy and methoxybenzoyloxy.
The C1-19 hydrocarbon group-substituting oxycarbonyloxy represented by R8 means a group in which oxycarbonyloxy is substituted by a C1-19 hydrocarbon group selected from the various hydrocarbon groups described above. Specific examples of such oxycarbonyloxy include methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy, heptyloxycarbonyloxy, octyloxycarbonyloxy, isopropyloxycarbonyloxy, isobutyloxycarbonyloxy, t-butyloxycarbonyloxy, isopentyloxycarbonyloxy and benzyloxycarbonyloxy.
A compound represented by General Formula (I) wherein R8 is acyloxy or hydrocarbon group-substituting oxycarbonyloxy corresponds to an ester of a compound represented by General Formula (I) wherein R8 is hydroxyl; the former compound is a prodrug designed for the purpose of improving the solubility, absorption and stability in the body of the latter compound. When metabolized in the body, the ester is converted into the compound in which R8 is hydroxyl, a real active substance.
A compound represented by General Formula (I) and its tautomer are chemically equivalent, and the purine derivative of the invention includes its tautomer. For example, when R8 is hydroxyl, a compound represented by General Formula (I) is a hydroxy derivative represented by General Formula (II): 
As a tautomer of the hydroxy derivative, there is an oxo derivative represented by General Formula (III): 
When R6 is hydroxyl, a compound represented by General Formula (I) is a hydroxy derivative represented by General Formula (IV): 
As a tautomer of the hydroxy derivative, there is an oxo derivative represented by General Formula (V): 
or General Formula (VI): 
As the purine derivative used in the invention, one preferable embodiment is an adenine derivative represented by General Formula (VII), (VIII) or (IX) below wherein R6 is amino or mono- or di-substituted amino: 
wherein R2, R8 and R9 are as defined in General Formula (I); 
wherein R2, R8 and R9 are as defined in General Formula (I); and R61 is a C1-10 hydrocarbon group; 
wherein R2, R8 and R9 are as defined in General Formula (I); and R61 and R62 independently represent a C1-10 hydrocarbon group.
In particular, the adenine derivative represented by General Formula (VII) is preferable. On the other hand, R8 is preferably hydroxyl or mercapto, more preferably, hydroxyl. Thus, 8-hydroxyadenine derivative represented by General Formula (X): 
wherein R2 and R9 are as defined in General Formula (I);
is more preferable compound. However, a compound represented by General Formula (VII) wherein R8 is acyloxy or hydrocarbon group-substituting oxycarbonyloxy can be regarded as comparable thereto in one sense since this compound corresponds to a prodrug of the compound represented by General Formula (X).
With respect to R2 and R9, preferable examples are as described above. In R9, selection of non-substituted or substituted benzyl is more preferable. Substituted benzyl as R9 includes such benzyl in which carbon in its benzene ring is substituted by nitrogen. The substituent on the ring includes chain hydrocarbon groups as side chains and groups derived therefrom having various structures such as ketone, aldehyde, carboxylic acid, ester, thioester, amide, carbonic acid ester, carbamic acid ester, sulfone, sulfonamide, ether, thioether, amine, alcohol, thiol or halogen structure derived as a result of substitution of CH2 by carbonyl, sulfonyl, O or S, or substitution of Cxe2x80x94H by N, C-halogen or Cxe2x80x94CN, as described previously. Among all, halogeno (especially fluoro, chloro and bromo), amino and halogeno-substituting alkyl are more preferable as substituted benzyl.
As R2, non-substituted or substituted alkyl, alkenyl, alkadienyl, cycloalkyl, aryl or aralkyl is more preferable. The substitution in these hydrocarbon groups include such substitution that derives structures such as ketone, aldehyde, carboxylic acid, ester, thioester, amide, carbonic acid ester, carbamic acid ester, sulfone, sulfonamide, ether, thioether, amine, alcohol, thiol or halogen structure as described above; and such substitution in which carbon constituting the ring skeleton of an aromatic ring is replaced by nitrogen. Among all, non-substituted or substituted lower alkyl, non-substituted or substituted benzyl, or non-substituted or substituted cycloalkylalkyl is more preferable.
Hereinbelow, methods of preparation of these purine derivatives will be described in detail.
(1) When R8 is OH or SH

With respect to a compound in which R2 is hydrogen and R6 is NH2, adenine is reacted with various substituted halide containing R9 (R9xe2x80x94X where X is halogen) in the presence of a base such as potassium carbonate, sodium hydroxide or sodium hydride to thereby substitute its position 9 to yield 9-substituted adenine derivative. As a solvent, dimethylformamide, dimethyl sulfoxide, or the like may be used. The solvent may be selected appropriately depending on the base. The reaction temperature may range from room temperature to about 80xc2x0 C. The resultant 9-substituted adenine derivative is reacted with bromine in the presence of a base such as sodium acetate to yield 9-substituted-8-bromoadenine derivative. As a solvent, acetic acid, chloroform, or the like may be used. The reaction temperature may range from room temperature to about 100xc2x0 C. Subsequently, when this 9-substituted-8-bromoadenine derivative is reacted with hydrochloric acid, a compound in which R8 is OH, i.e. 9-substituted-8-hydroxyadenine derivative can be prepared. The reaction temperature may range from room temperature to about 100xc2x0 C. Preferably, the reaction is performed under heating conditions, i.e. at 70-100xc2x0 C.
On the other hand, when the 9-substituted-8-bromoadenine derivative is reacted with NaSH, a compound in which R8 is SH, i.e. 9-substituted-8-mercaptoadenine derivative can be prepared. As a solvent, alcohol such as methanol or ethanol may be used. The reaction temperature may range from room temperature to a temperature at which the solvent is refluxed. Preferably, the reaction is performed under heating conditions.

With respect to a compound in which R2 is a substituent, 5-aminoimidazole-4-carboxamide is reacted with various substituted halide containing R9 (R9 xe2x80x94X where X is halogen) in the presence of a base such as sodium hydroxide or sodium hydride to thereby substitute its position 1 to yield 1-substituted-5-aminoimidazole-4-carboxamide. As a solvent, dimethylformamide, dimethyl sulfoxide, or the like may be used. The solvent may be selected appropriately depending on the base. The reaction temperature may range from room temperature to about 80xc2x0 C. When the resultant 1-substituted-5-aminoimidazole-4-carboxamide is reacted with R2 xe2x80x94COOEt, 2,9-disubstituted hypoxanthine derivative can be prepared. As a base, sodium ethoxide, sodium methoxide or the like may be used. As a solvent, alcohol such as methanol or ethanol may be used. The reaction temperature may range from room temperature to a temperature at which the solvent is refluxed. Preferably, the reaction is performed under heating conditions.
When this 2,9-disubstituted hypoxanthine derivative is brominated at position 8 and then hydrolyzed or reacted with NaSH in the same manner as described in a. above, a compound which has a substituent at positions 2 and 9 and OH at position 6 can be derived; i.e. 2,9-disubstituted-8-hydroxyhypoxanthine derivative or 2,9-disubstituted-8-mercaptohypoxanthine derivative can be prepared.
On the other hand, the above-mentioned 2,9-disubstituted hypoxanthine derivative is reacted with a chlorinating agent such phosphorus oxychloride or sulfonyl chloride to thereby yield 2,9-disubstituted-6-chloropurine. As a solvent, chloroform or the like may be used. Alternatively, the reaction may be performed without using any solvent. The reaction temperature may range from room temperature to about 100xc2x0 C. Preferably, the reaction is performed under heating conditions. The resultant 2,9-disubstituted-6-chloropurine is reacted with ammonia or various mono- or di-substituted amine to thereby yield 2,9-disubstituted adenine or 2,9-substituted-6N-substituted adenine. As a solvent, alcohol such as ethanol, dimethylformamide, dimethyl sulfoxide or the like may be used. The reaction temperature may range from room temperature to about 100xc2x0 C. Preferably, the reaction is performed under heating conditions. As a base, tertiary amine such as triethylamine may be used if necessary.
When the resultant 2,9-disubstituted adenine or 2,9-substituted-6N-substituted adenine is brominated at position 8 and then hydrolyzed or reacted with NaSH in the same manner as described in a. above, a compound which has a substituent at positions 2 and 9 and amino or substituted amino at position 6 can be derived; i.e. 2,9-substituted-8-hydroxyadenine or 2,9-substituted-8-mercaptoadenine or 2,9-substituted-6N-substituted-8-hydroxyadenine or 2,9-substituted-6N-substituted-8-mercaptoadenine can be derived.

When 5-amino-4-cyanoimidazole is reacted with R2CONH2, 2-substituted adenine can be derived. No solvent is necessary for this reaction. The two reactants are fused on heating. Preferably, the reaction temperature is high ranging from about 150 to about 240xc2x0 C. When this 2-substituted adenine is substituted at position 9, brominated and then hydrolyzed or reacted with NaSH in the same manner as described in b. above, a compound which has a substituent at positions 2 and 9 and amino at position 6 can be derived.

It is also possible to use other method known in the art for forming purine ring. For example, R2-containing amidine (which is the starting material) is reacted with malononitrile to yield a pyrimidine derivative. This derivative is reacted with sodium nitrate or mixed acid to thereby introduce nitro at position 5 of the pyrimidine and then reduced with Pd/C, Pt/C or the like to thereby convert the nitro into amino. It is also possible to react the resultant 2-substituted triaminopyrimidine with orthoester to thereby yield 2-substituted adenine. The subsequent procedures are the same as described in b. above.
(2) When R8 is Acyloxy or Alkoxycarbonyloxy
The purine derivative can be obtained by reacting the compound in which R8 is OH described in (1) above with acyl chloride or chloroformate R8 xe2x80x94Cl (which corresponds to a chloride of R8) in the presence of a base such as triethylamine, diisopropylethylamine or dimethylaminopyridine. As a solvent, tetrahydrofuran, 1,4-dioxane, dimethylformamide or the like may be used. The reaction temperature may range from room temperature to about 80xc2x0 C.
The thus obtained purine derivative (I) may also be used in the form of a pharmaceutical acceptable salt such as sodium salt, potassium salt, hydrochloride, hydrobromide, sulfate, nitrate, acetate, methanesulfonate, toluenesulfonate, citrate, etc.
In the Th2-selective immune response inhibitor and the immune response regulator of the invention, the purine derivative described above effectively treats or prevents those diseases attributable to abnormal rise in immune response on the Th2 side (i.e. allergic diseases such as asthma, allergic dermatitis or allergic rhinitis, or autoimmune diseases such as systemic lupus erythematosus) by inhibiting immune response on the Th2 side and enhancing immune response on the Th1 side. Thus, the immune response inhibitor and the immune response regulator of the invention can be administered for the purpose of treatment or prevention of those diseases. Besides, they are highly safe.
The pharmaceutical composition of the invention may be used in various dosage forms including oral preparations (such as tablets, capsules, powder), injections and external preparations. For example, the purine derivative which is the active ingredient of the pharmaceutical composition of the invention may be mixed with an excipient such as lactose, starch; a lubricant such as magnesium stearate, talc; and other conventional additives and then formulated into tablets. The amount of administration of the pharmaceutical composition of the invention is decided appropriately depending on the sex, age, body weight, disease to be treated, symptoms, etc. of a patient. Generally, the pharmaceutical composition of the invention in the form of an oral preparation is administered in the range from about 0.1 to about 100 mg/kg per day, preferably from about 0.1 to about 20 mg/kg per day, as a single dose or divided dose. In cases such as allergic dermatitis where diseased part is localized on the epidermis, the pharmaceutical composition of the invention may be used in the form of an external preparation such as ointment suitable for percutaneous absorption. In the case of bronchial asthma or allergic rhinitis, the pharmaceutical composition of the invention may also be used in the form of aerosol to be applied to the diseased part directly. The dosage of these local application preparations can be decided appropriately depending on the medium used.
Percutaneous absorbents, specifically ointments, to be applied to allergic dermatitis or the like may be prepared, for example, by the methods described below.
Water-soluble Ointment
A compound represented by General Formula (I) (1.0 g) is placed in a small-size stirring mixer. Pharmacopoeial macrogol ointment (99.0 g) heated to 70xc2x0 C. is added thereto and mixed for about 30 min under natural cooling. As a result, an ointment containing the compound of General Formula (I) as an active ingredient by 1% can be prepared.
Fat-soluble Ointment
A compound represented by General Formula (I) (1.0 g) is placed in a mortar. Liquid paraffin (18.5 g) is added thereto, and crushed and mixed sufficiently for about 5 min to thereby prepare a suspension. Subsequently, this suspension, white petrolatum (72 g) heated to 70xc2x0 C. and white beeswax (8.5 g) are placed in a small-size stirring mixer and mixed for about 30 min under natural cooling. As a result, an ointment containing the compound of General Formula (I) as an active ingredient by 1% can be prepared.
The anti-allergic agent of the invention comprising a purine derivative represented by General Formula (I) as an active ingredient is a medicine to be administered for the purpose of ameliorating the symptoms of allergic diseases caused by various factors, or for the purpose of preventing the manifestation of such symptoms. Specifically, the above-mentioned allergic diseases include allergic dermatitis, allergic rhinitis, atopic dermatitis and asthma (both atopic and non-atopic). The anti-allergic agent of the invention is used as a therapeutic or prophylactic for these diseases. Further, the immune response regulator of the invention comprising a purine derivative represented by General Formula (I) as an active ingredient is a drug which regulates helper T cell-involved immune responses into a desirable condition, utilizing the fact that the relevant purine derivative is an inhibitor of immune response on the Th2 side (e.g. IL-4 or IL-5 production) and, at the same time, an enhancer of interferon-xcex3 production by Th1. In the above-mentioned allergic diseases, for example, the immune response regulator of the invention is used in a comprehensive treatment aiming at reduction of patients"" burden by not only ameliorating allergic symptoms directly but also inhibiting various viral diseases which are frequently associated with those diseases. In autoimmune diseases such as systemic lupus erythematosus which exhibit similar uncomfortable symptoms, the immune response regulator of the invention may be used in a nosotropic treatment since the regulator selectively inhibits immune response on the Th-2 side. In particular, since it regulates helper T cell-involved immune responses so that a desirable condition will come, amelioration of symptoms as a whole can be achieved.